The general and long-term goal of my laboratory is to study autoantibody- mediated skin diseases in order to further our understanding not only of the pathophysiology of these diseases but also of the structure and function of normal epidermis. Specifically, we have found that autoantibodies from these patients, who develop blistering diseases due to defects in epidermal cell adhesion, are directed against adhesion molecules. We are characterizing, by immunochemical and molecular biologic means, the antigens defined by three of these diseases: bullous pemphigoid (BP), pemphigus vulgaris (PV), and pemphigus foliaceus (PF). This then allows us to study their cell biologic function. BP antigen is a component of the hemidesmosome, a basal-cell substrate adhesion junction. We have cloned cDNA with the full length coding sequence for this molecule. Analysis of its deduced amino acid sequence indicates that BP antigen has marked amino acid and structural homology with desmoplakin I, a desmosome plaque protein, and with plectin, a keratin-- associated protein. We have also determined that there is one gene encoding BP antigen and that it is grossly normal in patients with junctional epidermolysis bullosa, a hereditary disease with abnormal hemidesmosomes. We have also cloned cDNA with the full length coding sequence for PV antigen. The deduced amino acid sequence of this antigen indicates that it is in the cadherin family of calcium-dependent cell adhesion molecules and is closely related to the PF antigen. PV patients have antibodies against the aminoterminal domain of this molecule, an area thought to be important in its adhesion function, and these antibodies can cause loss of adhesion of epidermal cells in an animal model of disease.